Modulation of blood brain barrier permeability

Abstract

The present invention relates to a method of increasing blood brain barrier permeability in a subject. This method involves selecting a subject who would benefit from increased blood brain barrier permeability and subjecting the selected subject to a treatment. That treatment increases adenosine level and/or bioavailability, modulates adenosine receptors, and/or increases CD73 level and/or activity under conditions effective to increase blood brain barrier permeability in the subject. Methods of decreasing blood brain barrier permeability in a subject, treatment of a subject for a disorder or condition of the central nervous system, and screening compounds effective in increasing blood brain barrier permeability, as well as pharmaceutical agents are also disclosed.

1 . A method of increasing blood brain barrier permeability in a subject, said method comprising:
 selecting a subject who would benefit from increased blood brain barrier permeability, wherein said subject has a CNS disorder and   subjecting the selected subject to a treatment which modulates adenosine receptors and/or increases CD73 level and/or activity under conditions effective to increase blood brain barrier permeability in the subject.   
     
     
         2 . (canceled) 
     
     
         3 . The method of  claim 1 , wherein the selected subject is subjected to a treatment which modulates adenosine receptors. 
     
     
         4 . The method of  claim 3 , wherein an A 2a  adenosine receptor agonist is administered. 
     
     
         5 . The method of  claim 3 , wherein an A1 adenosine receptor antagonist is administered. 
     
     
         6 . The method of  claim 1 , wherein the selected subject is subjected to a treatment which increases CD73 level and/or activity. 
     
     
         7 . (canceled) 
     
     
         8 . The method of  claim 1 , wherein the CNS disorder is a psychiatric/behavioral disorder selected from the group consisting of schizophrenia, manic depression, dementia, and bipolar disorder. 
     
     
         9 . A method of decreasing blood brain barrier permeability in a subject, said method comprising:
 selecting a subject who would benefit from decreased blood brain barrier permeability and   subjecting the selected subject to a treatment which modulates adenosine receptors and/or decreases CD73 level and/or activity under conditions effective to decrease blood brain barrier permeability in the subject.   
     
     
         10 . (canceled) 
     
     
         11 . The method of  claim 9 , wherein the selected subject is subjected to a treatment which modulates adenosine receptors. 
     
     
         12 . The method of  claim 11 , wherein an A 2a  adenosine receptor antagonist is administered. 
     
     
         13 . The method of  claim 11 , wherein an A1 adenosine receptor agonist is administered. 
     
     
         14 . The method of  claim 9 , wherein the selected subject is subjected to a treatment which decreases CD73 level and/or activity. 
     
     
         15 . The method of  claim 9 , wherein the subject has an inflammatory disease. 
     
     
         16 . The method of  claim 9 , wherein the subject has a condition mediated by entry of lymphocytes into the brain. 
     
     
         17 .- 18 . (canceled) 
     
     
         19 . A method of treating a subject for a disorder or condition of the central nervous system, said method comprising:
 selecting a subject with the disorder or condition of the central nervous system;   providing a therapeutic effective to treat the disorder or condition of the central nervous system;   providing a blood brain barrier permeabilizing agent, wherein the agent modulates adenosine receptors and/or increases CD73 level and/or activity; and   administering to the selected subject the therapeutic and the blood brain barrier permeabilizing agent under conditions effective for the therapeutic to pass across the blood brain barrier and treat the disorder or condition.   
     
     
         20 .- 21 . (canceled) 
     
     
         22 . The method of  claim 19 , wherein the blood brain barrier permeabilizing agent modulates adenosine receptors. 
     
     
         23 . The method of  claim 22 , wherein an A 2a  adenosine receptor agonist is administered. 
     
     
         24 . The method of  claim 22 , wherein an A1 adenosine receptor antagonist is administered. 
     
     
         25 . The method of  claim 19 , wherein the blood brain barrier permeabilizing agent increases CD73 level and/or activity 
     
     
         26 . (canceled) 
     
     
         27 . A method of screening compounds effective in increasing blood brain barrier permeability, said method comprising:
 providing a modified animal with reduced CD73 expression levels, reduced adenosine expression levels, and/or modulated adenosine receptor activity compared to an unmodified animal;   providing one or more candidate compounds;   administering the one or more candidate compounds to the modified animal;   evaluating whether the one or more candidate compounds increases adenosine level and/or bioavailability, modulates adenosine receptors, and/or increases CD73 level and/or activity; and   identifying those candidate compounds which increase adenosine level and/or bioavailability, modulate adenosine receptors, and/or increase CD73 level and/or activity in the modified animal as being potentially effective in increasing blood brain barrier permeability.   
     
     
         28 . A pharmaceutical agent comprising:
 a therapeutic effective to treat the disorder or condition of the central nervous system and   a blood brain barrier permeabilizing agent, wherein the agent increases adenosine level and/or bioavailability, modulates adenosine receptors, and/or increases CD73 level and/or activity.   
     
     
         29 . (canceled)